Organ transplantation is the treatment of choice for patients with end-stage chronic diseases. In spite of the advancement in the improvement of transplantation techniques, the injury of the graft occurring during the ischemic period and subsequent reperfusion is still an unresolved problem in the clinical practice.
After removal from a donor and before graft transplantation into a recipient, the organ(s) and tissues are subjected to an inherent period of ischemia. Thus, the liquid solutions used to preserve the organs and tissues have to fulfil some requirements: removal of blood from donor, fast cool down the organ, and ensure effective prevention and protection against the lesions caused by ischemia.
Static hypothermic preservation is an effective method of organ preservation during short periods of ischemia. However, prolonged ischemia periods are associated with primary graft non-function in hepatic transplantation and with graft dysfunction in renal transplantation. Additionally to the need for extending the period of ischemia, the limited pool of donors and the subsequent increase in waiting list numbers for organ transplantation have led to the acceptance of marginal organs, which tolerate poorly the injury caused by a sustained ischemia. In the case of liver transplantation, the use of marginal organs such as steatotic grafts is associated with increased risk for primary non-function or dysfunction of the graft after the transplantation, compared with non-steatotic ones. In addition, some steatotic livers are considered not suitable for transplantation, exacerbating the shortage of organs for transplantation. It is well known that most of the injury showed by a marginal organ during transplantation is related to the period of hypothermic preservation. These observations indicate that the organ preservation must be optimized. Therefore, the main aim of organ preservation is trying to prolong organ tolerance to ischemia.
There is evidence indicating that the composition of preservation solutions is a critical factor for the quality of organs kept for prolonged ischemic periods. University of Wisconsin (UW) preservation solution is considered the standard solution for liver preservation since it has proved itself effective in reducing damage caused by cold ischemia and has extended storage time limits. This preservation solution contains different components directed to enhance organ preservation including the colloid hydroxyethyl starch to prevent cell oedema, adenosine as a source of ATP on reperfusion, allopurinol and glutathione with antioxidant effects and cell membrane-impermeant agents such as lactobionic acid and raffinose. However, this preservation solution, UW, has limitations regarding the efficacy since irreversible injuries have been observed in transplanted organs when cold ischemic periods are prolonged (16 h-24 h).
Tacrolimus (TCR) is a macrolide compound with effective immunosuppressive activity, antimicrobial activity and other pharmacological activities and is of value for the prevention of rejection reactions on transplantation of organs and tissues as well as for autoimmune disorders and infectious disorders. It is known that its addition to preservation solutions can protect against reperfusion injury. A UW preservation solution containing tacrolimus has been described in the literature (K. G. Rajesh et al., “Mitochondrial Permeability transition-pore inhibition enhances functional recovery after long-time hypothermic heart preservation”, Transplantation, 2003, vol. 76 (9), pp. 1314-20). Its action on the preservation of hearts was assayed. Nevertheless, it was concluded that tacrolimus failed to have any effect on preservation.
Carvedilol (CVD) is a lipophilic nonselective β-adrenergic blocker with vasodilator effects exerted primarily through selective al receptor blockade and with a strong antioxidant effect. The capacity of carvedilol to inhibit lipid peroxidation is much greater than that of other tested β-adrenergic blockers, which may explain its superior protective effects in ischemia/reperfusion models. Although the addition of antioxidants, such as carvedilol, to preservation solutions has been suggested in the literature (cf. B. Yard et al., “Prevention of cold-preservation injury of cultured endothelial cells by catecholamines andrelated compounds”, American Journal of transplantation, 2004, vol. 4, pp. 22-30), no specific preservation solution comprising carvedilol has ever been disclosed.
A recent work indicates that the addition of trimetazidine (TMZ) to the UW preservation solution improved the capacity of this standard preservation solution to protect both in non-steatotic and, especially, in steatotic livers subjected to prolonged ischemic periods (cf. I. Ben Mosbah et al. “Trimetazidine: Is it a promising drug for use in steatotic grafts?”, World J Gastroenterol, 2006, vol. 12(6), pp. 908-914).
Nevertheless, some of the properties of UW solution, such as high potassium concentration (required to flush the organ before graft reperfusion in the recipient) and the presence of hydroxyethyl starch (HES) as oncotic support (which could be responsible for red blood cell aggregation) do not favour the organ preservation. Recent studies have demonstrated that both liver grafts (steatotic and non-steatotic grafts) are better preserved in a modified UW preservation solution (called IGL-1), characterized by the inversion of K+ and Na+ concentrations and the replacement of HES by polyethylene glycol (PEG) in the original UW solution (cf. I. Ben Mosbah et al., “Preservation of steatotic livers in IGL-1 solution”, Liver Transpl, 2006, vol. 12 (8), pp. 1215-23). On the other hand, despite the improvements offered by IGL-1 solution, the deleterious effects of ischemia-reperfusion (I/R) remain unresolved.
There is still a need of finding preservation solutions which allow prolonging organ tolerance to ischemia and minimizing the inherent risk of marginal organs subjected to transplantation.